1. Field of the Invention
The invention relates to mediation of specific cytokine induction. More particularly, the invention relates to modulating specific cytokine expression in vivo.
2. Summary of the Related Art
Cell-mediated immunity (CMI) is an important mechanism for host defense against a broad range of infectious diseases. CMI is largely controlled through expression of specific cytokines. Le and Vilcek, Laboratory Investigation 61: 588-602 (1989) teaches that the cytokine IL-6, produced mostly by B-lymphocytes, monocytes and Th2 cells, promotes release of acute phase reactants and contributes to T cell activation. Trinchieri et al., Ann. Rev. Immunol. 13: 252-276 (1995) and Res. Immunol. 146: 419-656 (1995) disclose that the recently discovered cytokine IL-12 is critical to the initiation of CMI.
IL-12 most likely acts first upon resting natural killer (NK) cells, which express the IL-12 receptor. Gazzinelli et al., Proc. Natl. Acad. Sci. USA 90: 6115-6119 (1993) teaches that upon stimulation with IL-12, NK cells produce high levels of IFN-gamma, which is a potent stimulator of macrophage effector functions against invasive pathogens, and which further enhances IL-12 synthesis by macrophages previously triggered by an infectious agent.
At another level, IL-12 appears to act by driving the differentiation of T helper cell precursors (Thp) toward production of Th1 cells, which produce IL-2, IFN-gamma and TNF-beta, thereby driving the CMI response. Seder et al., teaches that this process begins by recognition of specific antigen by Thp, which produces IL-2 and subsequently IL-12 receptor. The Thp cell then differentiates into a Th1 cell if IL-12 is present, or into a Th2 cell in an IL-4 environment. Gazzineri et al., J. Immunol. 153: 2533-2543 (1994) teaches that the Th1 cells, once differentiated, do not require IL-12 as a co-stimulatory molecule to produce cytokines and mediate resistance against pathogens.
Miller and Krangel, Crit. Rev. Immunol. 12: 17-46 (1992) and Taub et al., J. Clin. Invest. 95: 1370-1376 (1995) teach that chemokines are one superfamily of cytokines that play important roles in recruitment and activation of lymphocytes to sites of inflammation. Gallo et al., Science 274: 1393-1395 (1996) teaches that certain chemokines, such as RANTES, MIP-1α and MIP-1β can suppress the replication of macrophage-tropic HIV strains in infected T cell cultures, and therefore may play important roles in the regulation of virus replication and are potentially useful as anti-viral therapeutics.
During bacterial infections, the natural immune response is characterized by the production of various cytokines which are involved in CMI. Uyttenhove et al., J. Exp. Med. 167: 1417-1427 (1988) teaches that IL-6 production is stimulated by bacterial infection. Murray, Diagn. Microbiol. Infect. Dis. 13: 411-421 (1990) teaches that IFN-gamma is produced in response to bacterial infection. Trinchieri, Blood 84: 4008-4027 (1994) discloses IL-12 induction resulting from bacterial infection.
The bacterial components responsible for such cytokine induction have recently been investigated. Yamamoto et al., Microbiol. Immunol. 36: 983-997 (1992) showed that bacterial DNA, but not mammalian DNA, boosts lytic activity of NK cells as well as IFN-gamma production, and proposed that this effect was caused by palindromic sequences present in bacterial DNA. More recently, Klinman et al., Proc. Natl. Acad. Sci. USA 93: 2879-2883 (1996) discloses that the ex vivo induction of IL-6, IL-12 and IFN-gamma by bacterial DNA is mediated by a structural motif of an unmethylated CpG dinucleotide preceded by two purines and followed by two pyrimidines and that this effect can be duplicated by an oligonucleotide of at least eight nucleotides containing such a structural motif. These authors noted that such effects may confound studies involving antisense, gene therapy, or plasmid DNA vaccines produced in bacteria.
Interest in developing drugs modeled from microbial products that induce CMI has been expressed. Gazzinelli, Molecular Medicine Today, June 1996, pp. 258-267, notes that such compounds would have a broad application in immunotherapy. However, Gazzinelli also teaches that uncontrolled IL-12 synthesis may cause excessive activation of the immune system, resulting in severe host tissue damage and death Gazzinelli concludes such toxicity is likely to limit the use of IL-12 therapy in humans.
There is, therefore, a need for new approaches to modulating specific CMI-inducing cytokines in vivo. Such approaches should stimulate production of the desired cytokines without substantially inducing undesired cytokines and without causing unwanted toxic side effects. Ideally, such approaches should protect against infection by a pathogenic agent or against tumor development.